NRX-0492 degrades wild-type and C481 mutant BTK and demonstrates in vivo activity in CLL patient-derived xenografts.

Bruton tyrosine kinase (BTK) is essential for B-cell receptor (BCR) signaling, a driver of chronic lymphocytic leukemia (CLL). Covalent inhibitors bind C481 in the active site of BTK and have become a preferred CLL therapy. Disease progression on covalent BTK inhibitors is commonly associated with C481 mutations. Here, we investigated a targeted protein degrader, NRX-0492, that links a noncovalent BTK-binding domain to cereblon, an adaptor protein of the E3 ubiquitin ligase complex. NRX-0492 selectively catalyzes ubiquitylation and proteasomal degradation of BTK. In primary CLL cells, NRX-0492 induced rapid and sustained degradation of both wild-type and C481 mutant BTK at half maximal degradation concentration (DC50) of ≤0.2 nM and DC90 of ≤0.5 nM, respectively. Sustained degrader activity was maintained for at least 24 hours after washout and was equally observed in high-risk (deletion 17p) and standard-risk (deletion 13q only) CLL subtypes. In in vitro testing against treatment-naïve CLL samples, NRX-0492 was as effective as ibrutinib at inhibiting BCR-mediated signaling, transcriptional programs, and chemokine secretion. In patient-derived xenografts, orally administered NRX-0492 induced BTK degradation and inhibited activation and proliferation of CLL cells in blood and spleen and remained efficacious against primary C481S mutant CLL cells collected from a patient progressing on ibrutinib. Oral bioavailability, >90% degradation of BTK at subnanomolar concentrations, and sustained pharmacodynamic effects after drug clearance make this class of targeted protein degraders uniquely suitable for clinical translation, in particular as a strategy to overcome BTK inhibitor resistance. Clinical studies testing this approach have been initiated (NCT04830137, NCT05131022).

Medical Student Duty Hours and Shelf Performance: Is There a Correlation?

OBJECTIVE: To date, there is limited information about medical student duty hours, shelf scores, and overall clerkship performance in obstetrics and gynecology (OB/GYN). As a result, we were curious to know whether spending more time in the clinical environment translated to an improved learning experience or, in contrast, translated to decreased study time and worse overall clerkship performance. STUDY DESIGN: A retrospective cohort analysis was performed at a single academic medical center of all medical students on the OB/GYN clerkship from August 2018 to June 2019. Recorded student duty hours were tabulated per day and per week, by student. National Board of Medical Examiners (NBME) Subject Exam (Shelf) equated percentile scores for the quarter of year were used. RESULTS: Our statistical analysis showed that working long hours did not translate to higher or lower shelf score, or higher overall clerkship grade. However, working longer hours in the last 2 weeks of the clerkship was associated with high shelf score. CONCLUSION: Longer medical student duty hours did not correlate to higher shelf scores or overall clerkship grades. Future multicenter studies are necessary to evaluate the importance of medical student duty hours and continue optimizing the educational experience of the OB/GYN clerkship. KEY POINTS: · Clinical hours were not associated with shelf examination scores.. · Clinical hours were not associated with overall clerkship grade.. · Longer clinical hours at the end of clerkship are correlated with higher examination scores..

Clinical and biological implications of target occupancy in CLL treated with the BTK inhibitor acalabrutinib.

Inhibition of the B-cell receptor pathway, and specifically of Bruton tyrosine kinase (BTK), is a leading therapeutic strategy in B-cell malignancies, including chronic lymphocytic leukemia (CLL). Target occupancy is a measure of covalent binding to BTK and has been applied as a pharmacodynamic parameter in clinical studies of BTK inhibitors. However, the kinetics of de novo BTK synthesis, which determines occupancy, and the relationship between occupancy, pathway inhibition and clinical outcomes remain undefined. This randomized phase 2 study investigated the safety, efficacy, and pharmacodynamics of a selective BTK inhibitor acalabrutinib at 100 mg twice daily (BID) or 200 mg once daily (QD) in 48 patients with relapsed/refractory or high-risk treatment-naïve CLL. Acalabrutinib was well tolerated and yielded an overall response rate (ORR) of partial response or better of 95.8% (95% confidence interval [CI], 78.9-99.9) and an estimated progression-free survival (PFS) rate at 24 months of 91.5% (95% CI, 70.0-97.8) with BID dosing and an ORR of 79.2% (95% CI, 57.9-92.9) and an estimated PFS rate at 24 months of 87.2% (95% CI, 57.2-96.7) with QD dosing. BTK resynthesis was faster in patients with CLL than in healthy volunteers. BID dosing maintained higher BTK occupancy and achieved more potent pathway inhibition compared with QD dosing. Small increments in occupancy attained by BID dosing relative to QD dosing compounded over time to augment downstream biological effects. The impact of BTK occupancy on long-term clinical outcomes remains to be determined. This trial was registered at www.clinicaltrials.gov as #NCT02337829.

Risk Factors for Adverse Maternal Outcomes following Expectantly Managed Preterm Prelabor Rupture of Membranes.

OBJECTIVE: We sought to characterize the incidence and risk factors associated with developing maternal morbidity following preterm prelabor rupture of membranes. STUDY DESIGN: Retrospective case-control study of patients with preterm prelabor rupture of membranes at a single institution from 2013 to 2019 admitted at ≥23 weeks gestational age. The primary outcome was a composite of maternal morbidity which included: death, sepsis, intensive care unit (ICU) admission, acute kidney injury, postpartum dilation and curettage, postpartum hysterectomy, venous thromboembolism, postpartum hemorrhage, postpartum wound complication, postpartum endometritis, pelvic abscess, postpartum pneumonia, readmission, and/or need for blood transfusion were compared with patients without above morbidities. Severe morbidity was defined as: death, ICU admission, venous thromboembolism, acute kidney injury, postpartum hysterectomy, sepsis, and/or transfusion >2 units. Demographics, antenatal, and delivery characteristics were compared between patients with and without maternal morbidity. Bivariate statistics and regression models were used to compare outcomes and calculate adjusted odd ratios. RESULTS: Of 361 included patients, 64 patients (17.7%) experienced maternal morbidity and nine (2.5%) had severe morbidity. Patients who experienced maternal morbidity were significantly (p < 0.05) more likely to be older, have private insurance, have BMI ≥40, have chorioamnionitis at delivery, and undergo cesarean or operative vaginal delivery when compared with patients who did not experience morbidity. After controlling for confounders, cesarean delivery (aOR 2.38, 95% CI[1.30,4.39]), body mass index ≥40 at admission (aOR 2.54, 95% CI[1.12,5.79]), private insurance (aOR 3.08, 95% CI[1.54,6.16]), and tobacco use (aOR 3.43, 95% CI[1.58,7.48]) were associated with increased odds of maternal morbidity. CONCLUSION: In this cohort, maternal morbidity occurred in 17.7% of patients with preterm prelabor rupture of membranes. Private insurance, body mass index ≥40, tobacco use, and cesarean delivery were associated with higher odds of morbidity. These data can be used in counseling and to advocate for smoking cessation. KEY POINTS: · 17.7% of patients with PPROM experienced maternal morbidity.. · BMI ≥40 was associated with higher odds of maternal morbidity.. · Tobacco use and cesarean delivery were associated with higher odds of maternal morbidity..

Beta-blocker and ACE-inhibitor dosing as a function of body surface area: From the HF-ACTION trial.

Recognizing that body surface area (BSA) is a commonly used metric to inform medication dosing across fields of medicine, it is possible that patients with heart failure with reduced ejection fraction (HFrEF) with higher BSA may be more likely to tolerate higher doses of GDMT. Using the HF-ACTION trial, we examined (1) the relationship between BSA and achievement of target dosing of evidence-based beta-blocker and angiotensin-converting enzyme inhibitor (ACEI) therapy, and (2) the associations and interactions between target dosing, clinical outcomes, and BSA.